Azithromycin is an antibiotic which is administered orally or intravenously, to treat various infections, particularly infections of the urinary tract, bronchial tract, lungs, sinuses and the middle ear.
Oral dosing of azithromycin can result in adverse gastrointestinal (GI) side effects such as nausea, cramping, diarrhea and vomiting in a significant number of patients. Such GI side effects can also occur in non-human mammals, e.g., dogs. In combined clinical studies of azithromycin involving 3,995 human patients (all dose levels combined), 9.6% of patients reported GI side effects; the most frequent of these side effects were diarrhea (3.6%), nausea (2.6%), and abdominal pain (2.5%) Hopkins, 91 Am. J. Med. 40S (suppl 3A 1991).
The frequency of these adverse effects increase with higher dose levels of azithromycin. In treating adult humans, for a single 1 gram dose, administered in an oral suspension, the reported incidence of various GI side effects was 7% diarrhea/loose stools, 5% nausea, 5% abdominal pain, and 2% vomiting (U.S. Package Insert for Zithromax® azithromycin for oral suspension). However, for a single 2 gram, administered in an oral suspension, the reported incidence of various GI side effects was 14% diarrhea/loose stools, 7% abdominal pain, and 7% vomiting (Ibid.).
Similarly, in treating pediatric humans, by administering an oral suspension containing 10 mg/kg on Day 1 and 5 mg/kg on days 2–5, the reported incidence of various GI side effects was 4% diarrhea/loose stools, 2% abdominal pain, and 2% vomiting (Ibid.), while, for a single 30 mg/kg dose, administered in an oral suspension, the reported incidence of various GI side effects was 6.4% diarrhea/loose stools, 1.7% nausea, and 4% vomiting (Ibid.).
Antacids, which are alkalizing agents that are provided in large doses to raise stomach pH from about 1–3 to about 4–7, may provide a patient with relief from diarrhea, cramping, and gastric upset. However, patients have been cautioned against simultaneously taking an antacid, particularly those containing aluminum or magnesium, with azithromycin, as antacids have been shown to reduce azithromycin maximum serum concentration Cmax by 24% (Ibid.). Further, to avoid antacid caused interference with azithromycin absorption, patients have also been advised to separate the administration of azithromycin and antacid doses by at least two hours.
Presently, small amounts, about 132 mg or less, of the alkalizing agent anhydrous tribasic sodium phosphate are used in commercial dosage forms of azithromycin to mask the bitter taste of azithromycin by reducing the solubility of azithromycin before swallowing. Further, in treating uncomplicated gonococcal infections, two single dose packets of azithromycin, which each contain 88 mg of anhydrous tribasic sodium phosphate, are concurrently administered in a single dose to a patient in need thereof.
More recently, azithromycin controlled release dosage forms have been prepared, as described in U.S. Pat. No. 6,068,859, that reduce the gastrointestinal side effects, resulting from an administered dose of azithromycin, as compared to an equivalent dose of commercial immediate release azithromycin capsules. However, the bioavailability of many of the controlled release dosage forms, specifically exemplified therein, were subsequently found to be less than their immediate release equivalents.
Therefore, what is needed is an azithromycin dosage form that has a bioavailability similar to, and gastrointestinal side effects less than, an equivalent dose of immediate release azithromycin.